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Posted: November 18, 2009

Illumination activates compounds with therapeutic potential

(Nanowerk News) Proteins that can switch between closed and open states control the passage of electrically charged ions across cell membranes, and are responsible for the generation and propagation of nerve impulses. Chemicals that influence the structural state of such ion channels, and thus perturb neural activity, find use as psychoactive drugs and as anaesthetics.

In the latest issue of the international edition of Angewandte Chemie, Professor Dirk Trauner of LMU Munich’s Department of Chemistry and Biochemistry, together with colleagues at the University of California in Berkeley, describes a new type of molecule that activates so-called voltage-gated potassium channels when exposed to light of a certain colour ("Photochromic Blockers of Voltage-Gated Potassium Channels"). These molecules could have therapeutic potential in the treatment of some forms of blindness and other diseases.

Ligand-gated channels in cell membranes can be opened by specific chemicals. A nerve impulse is set off by neurotransmitters that open ligand-gated channels on the membrane to allow inflow of sodium ions (Na+). In effect, this causes a wave of depolarization that passes down the cell membrane to the nerve terminals, where it triggers the release of neurotransmitter to activate neighbouring neurons. Professor Trauner and his team have studied a voltage-gated channel that is opened by changes in the electric field in their immediate vicinity. This protein, a potassium (K+) channel called Shaker, opens shortly after depolarization: Passage of K+ ions out of the cell compensates for the influx of Na+, helping to restore membrane polarization and returning the sodium channels to their closed state, ready to respond to the next stimulus.

Trauner’s team have previously designed and synthesized photo-activatable chemicals that spontaneously attach to channel proteins. Exposure to light of a specific colour causes such a compound to extend into the natural ligand-binding pocket, opening the channel and initiating a nerve impulse. In a recent publication, Trauner reports how the Shaker channel can be blocked and unblocked using light. “It was known that Shaker has an external binding site for the inhibitor tetraethylammonium or TEA, and we expected our ligand, called AAQ, to attach there”, he says. But the experiments indicated that AAQ did not bind covalently to the channel, although it was effective as a blocker when applied extracellularly. Shaker, however, also has an internal binding site for TEA, which is accessible from the outside only when the channel is open.

When the researchers added AAQ to cells under irradiation with 380-nm light, the channel responded normally to membrane depolarization. But when they did the same experiment under 500-nm light, they observed a burst of current, followed by long-lasting inhibition of ion flow. “We concluded that AAQ can permeate into the open channel,” Trauner says. “Irradiation at 500-nm then causes it to bind to the internal site, blocking the pore.” Derivatives of AAQ could have therapeutic potential in the treatment of eye diseases. It might even serve as the basis for a topically applicable, photoactivatable anaesthetic, making visits to the dentist a pleasure.